Nitric oxide inhibits H2O2-induced transferrin receptor-dependent apoptosis in endothelial cells: Role of ubiquitin-proteasome pathway

We investigated here the mechanism of cytoprotection of nitric oxide ( • NO) in bovine aortic endothelial cells treated with H 2 O 2 . NONOates were used as • NO donors that released • NO slowly at a well defined rate in the extracellular and intracellular milieus. H 2 O 2 -mediated intracellular di...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 19; pp. 10653 - 10658
Main Authors:	Kotamraju, Srigiridhar, Tampo, Yoshiko, Keszler, Agnes, Chitambar, Christopher R, Joseph, Joy, Haas, Arthur L, Kalyanaraman, B
Format:	Journal Article
Language:	English
Published:	United States National Acad Sciences 16-09-2003 National Academy of Sciences
Subjects:	Aconitate Hydratase - metabolism Animals Apoptosis - physiology Biochemistry Biological Sciences Cattle Cells Cysteine Endopeptidases - metabolism Endothelium, Vascular - cytology Endothelium, Vascular - metabolism Fluorescence Glutathione - metabolism Hydrogen Peroxide - antagonists & inhibitors Hydrogen Peroxide - metabolism Iron Regulatory Protein 1 - metabolism Multienzyme Complexes - metabolism Nitric oxide Nitric Oxide - physiology Oxidative Stress Proteasome Endopeptidase Complex Receptors, Transferrin - physiology Ubiquitin - metabolism
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Summary:	We investigated here the mechanism of cytoprotection of nitric oxide ( • NO) in bovine aortic endothelial cells treated with H 2 O 2 . NONOates were used as • NO donors that released • NO slowly at a well defined rate in the extracellular and intracellular milieus. H 2 O 2 -mediated intracellular dichlorofluorescein fluorescence and apoptosis were enhanced by the transferrin receptor (TfR)-mediated iron uptake. • NO inhibited the TfR-mediated iron uptake, dichlorofluorescein fluorescence, and apoptosis in H 2 O 2 -treated cells. • NO increased the proteasomal activity and degradation of nitrated TfR via ubiquitination. N ω -nitro- l -arginine methyl ester, a nonspecific inhibitor of endogenous • NO biosynthesis, decreased the trypsin-like activity of 26S proteasome. • NO, by activating proteolysis, mitigates TfR-dependent iron uptake, dichlorodihydrofluorescein oxidation, and apoptosis in H 2 O 2 -treated bovine aortic endothelial cells. The relevance of biological nitration on redox signaling is discussed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Communicated by Helmut Beinert, University of Wisconsin, Madison, WI, June 26, 2003 Abbreviations: Tf, transferrin; TfR, Tf receptor; IRP, iron-regulatory protein; Ub, ubiquitin; MG-132, N-carbobenzoxyl-l-leucinyl-l-leucinyl-l-norleucinal; GO, glucose oxidase; Lac, clasto-lactacystin-β-lactone; DCFH, dichlorodihydrofluorescein; DA, diacetate; DETA/NO, diethylenetriamine NONOate; AcOM-PYRRO, pyrrolidine nonoate methylene acetate; BAEC, bovine aortic endothelial cell; GSH, glutathione; IRE, iron-responsive element; DCF, dichlorofluorescein; l-NAME, Nω-nitro-l-arginine methyl ester; NOS, NO synthase. To whom correspondence should be addressed at: Biophysics Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: balarama@mcw.edu.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1933581100